Early Life Stress and Immune Dysfunction in Post-Institutionalized Adolescents

收容后青少年的早期生活压力和免疫功能障碍

• 批准号: 9117228
• 负责人: CHRISTOPHER L COE
• 金额: $ 24.17万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-19 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117228
• 关键词: 17 year old; Accounting; Address; Adolescence; Adolescent; Adopted; Adoption; Adrenal Glands; Adult; Affect; American; Animal Model; B-Lymphocytes; Behavioral; Biological Assay; Biology; Bioperiodicity; Blood Circulation; Blood specimen; Brain; C-reactive protein; CD28 gene; CD3 Antigens; CD8B1 gene; Caring; Cells; Child; Child health care; Childhood; Circadian Rhythms; Color; Competence; Complete Blood Count; Country; Cultured Cells; Data; Development; Diagnostic tests; Eastern Europe; Endotoxins; Event; Family; Feedback; Goals; Health; Hormones; Human; Hydrocortisone; Hypothalamic structure; Immune; Immune System Diseases; Immune Targeting; Immune response; Immune system; Immunity; Immunophenotyping; Impaired health; In Vitro; Individual; Infant; Infection; Inflammatory; Institution; Institutionalized Adolescent; Intervention; Learning; Life; Life Stress; Link; Literature; Longevity; Lymphocyte; Lymphocyte Subset; Measures; Mediating; Mental Health; Mononuclear; Neurosecretory Systems; Orphanages; Parents; Pattern; Phase; Phenotype; Pituitary Gland; Population; Preventive care; Principal Investigator; Public Health; Reaction; Recording of previous events; Recovery; Regulation; Research; Risk; Russia; Saliva; Sample Size; Severities; Shapes; Signal Transduction; Stress; System; T cell differentiation; T-Lymphocyte; Teenagers; Testing; UNICEF; Variant; Work; Youth; abuse neglect; adopted child; base; cytokine; deprivation; directed attention; experience; immune function; improved; infancy; innovation; neglect; preclinical study; prenatal; prevent; programs; public health relevance; resilience; response; trafficking

 DESCRIPTION (provided by applicant): There is a dearth of evidence in humans definitively showing that stress confined to the prenatal-infancy period has programming-like effects on the immune system. In addition, human studies of immune correlates of adverse childhood conditions have not focused specifically T-cell phenotypes involved in immune regulation that may compromise the ability to respond to infection. Both of these gaps in the literature are highly significant in that they limit our ability to understand the mechanisms through which early life stress (ELS) impairs health across the life span. This R21 addresses these lacunae by conducting sophisticated immunophenotyping and functional immune assays in a unique population of youth (14 through 17 years of age) who as infants (< 36 months) were adopted from orphanages/institutions in Russia/Eastern Europe into well-resourced and generally stable, low-life-stress families in the US. The early life stress (ELS) for these youth, thus, was confined to the prenatal-infancy period. There are two aims. Aim 1: Determine the impact of ELS on immune responses of these youth now that they are adolescents. Blood samples will be obtained from 30 post-institutionalized (PI) and 30 comparison adolescents. Sophisticated multi-color immunophenotyping will be used to characterize lymphocyte subsets and mononuclear cell responses will be probed in vitro with stimulants, and cytokine levels in supernatants determined with multi-cytokine arrays. Complete blood counts and C-reactive protein levels also will be determined. Saliva cortisol collected at testing will assess whether transient cortisol elevations in response to blood sampling contribute to the immune differences between groups. Aim 2. Delineate factors that account for differential vulnerability among ELS youth, including distorted hormone biorhythms and severity of the ELS. The second phase of this project will expand the sample size to include 30 additional PI's (total=60), providing sufficient diversity to determine the influence of the severity and duration of institutional care and the mediating influence of dysregulated HPA diurnal rhythms to predict variation in the T cell repertoire and cellular responses in stimulated cultures. This work is highly significant because, by focusing on youth who experience radical improvements in care post-infancy, it will provide the strongest evidence to date of prenatal-infancy programming-like effects on the human immune system and underscores the importance of preventing early deprivation and neglect. It also has potential significance for improving the preventive care of individuals with a history of early adverse care, by delineating specific immune alterations that may underlie potential health risks later in adulthood. It is highly innovative in being the first study of ELS in humans to employ such a sophisticated immune panel and to combine measures that are integral to a pro-inflammatory bias and immune competence. This R21 project will lay the groundwork for a new avenue of ELS-immune research that is focused on lingering sequelae of childhood experiences.

 描述（由申请人提供）：缺乏人类证据明确表明产前婴儿期的压力对免疫系统具有类似编程的影响。此外，对儿童期不良疾病的免疫相关性的人类研究没有特别关注参与免疫调节的T细胞表型，这可能会损害对感染的反应能力。文献中的这两个空白都非常重要，因为它们限制了我们理解早期生活压力（ELS）在整个生命周期中损害健康的机制的能力。该R21通过在一个独特的青年人群（14至17岁）中进行复杂的免疫表型分析和功能性免疫测定来解决这些缺陷，这些青年在婴儿（< 36个月）时从俄罗斯/东欧的孤儿院/机构收养到美国资源充足且通常稳定的低生活压力家庭。因此，这些年轻人的早期生活压力（ELS）被限制在 到产前婴儿期。有两个目标。目标1：确定ELS对这些青少年免疫反应的影响，因为他们是青少年。将从30名住院后（PI）和30名对照青少年中采集血样。将使用复杂的多色免疫表型分析来表征淋巴细胞亚群，并将在体外用刺激剂探测单核细胞应答，并用多细胞因子阵列测定上清液中的细胞因子水平。还将测定全血细胞计数和C反应蛋白水平。测试时采集的唾液皮质醇将评估血液采样后皮质醇一过性升高是否会导致组间免疫差异。目标2.描述导致ELS青年不同脆弱性的因素，包括激素生物节律紊乱和ELS的严重程度。该项目的第二阶段将扩大样本量，以包括30个额外的PI（总计=60），提供足够的多样性，以确定机构护理的严重程度和持续时间的影响以及HPA昼夜节律失调的介导影响，以预测刺激培养物中T细胞库和细胞反应的变化。这项工作非常重要，因为通过关注在婴儿期后护理方面经历了根本性改善的青年，它将提供迄今为止最有力的证据，证明产前-婴儿期规划对人类免疫系统的影响，并强调预防早期剥夺和忽视的重要性。它也有潜在的意义，以改善个人的预防性护理与早期不良护理的历史，通过描绘特定的免疫改变，可能是潜在的健康风险，在成年后。这是第一次在人类中进行ELS研究，采用如此复杂的免疫组，并结合联合收割机措施，这些措施是促炎性偏倚和免疫能力的组成部分，这是非常创新的。这个R21项目将为ELS免疫研究的新途径奠定基础，该研究的重点是童年经历的后遗症。